1. Field of the Invention
The present invention relates to the synthesis of degradable polymers. More particularly, the present invention relates to degradable polymers having increased functionality.
2. Related Art
Interest in the synthesis of new degradable polymers has expanded in recent years. This increased interest stems in part from the concern that the extensive and continuing use of polymers in today""s society will result in environmental damage. The concern is that many polymers used in commercial applications are inert and thus able to withstand natural processes that cause other non-inert materials to disintegrate and decompose. As a result of this inertness, polymers have accumulated in landfills and thereby have contributed to the shortage of landfill space generally. This problem will only be exacerbated as polymers are used in more and more commercial products and services. Thus, there is a need for developing polymers for commercial applications that have an enhanced ability to degrade.
The increased interest in the synthesis of new degradable polymers also stems in part from the use of synthetic polymers in medical applications. In medical applications, not only must the polymer be able to degrade, but the degradation products also must be compatible with the human body, i.e., be nontoxic. In this situation, the polymers are termed biodegradable, indicating their ability to degrade due to biological processes occurring inside the human body. As early as the 1960s, synthetic polymers were used in the field of surgical medicine as suture material. The polymeric suture material was both biodegradable and absorbable, that is, the polymers decomposed after a period of time after implantation in the human body, and those decomposition products were absorbed by the human body without any adverse or toxic effects. The advantage of biodegradable polymer-based suture materials is the ability to fabricate fibers with varying absorption rates to match the healing profiles of the tissues they help to repair. Another advantage of such polymer-based sutures over traditional silk and gut sutures is enhanced versatility and low tissue reactivity.
In addition to use as suture material, degradable polymers have been used in other biomedical applications, such as polymer-based drug delivery systems. In such a system, degradable polymers are used as a matrix for the controlled or sustained delivery or release of biologically active agents, such as, drugs, to the human body. In addition, the development of endoscopic surgical techniques has resulted in the need for developing such degradable drug delivery systems wherein the placement of the drug delivery device is targeted for specific anatomical locations. Examples of such polymer-based drug delivery systems are described in the following U.S. patents: U.S. Pat. No. 6,183,781, entitled xe2x80x9cMethod for Fabricating Polymer-based Controlled-release Devicesxe2x80x9d; U.S. Pat. No. 6,110,503, entitled xe2x80x9cPreparation of Biodegradable, Biocompatible Microparticles Containing a Biologically Active Agentxe2x80x9d; U.S. Pat. No. 5,989,463, entitled xe2x80x9cMethods for Fabricating Polymer-based Controlled-release Devicesxe2x80x9d; U.S. Pat. No. 5,916,598, entitled xe2x80x9cPreparation of Biodegradable, Biocompatible Microparticles Containing a Biologically Active Agentxe2x80x9d; U.S. Pat. No. 5,817,343, entitled xe2x80x9cMethod for Fabricating Polymer-based Controlled-release Devicesxe2x80x9d; U.S. Pat. No. 5,650,173, entitled xe2x80x9cPreparation of Biodegradable, Biocompatible Microparticles Containing a Biologically Active Agent.xe2x80x9d Other examples of polymer-based drug delivery systems are described in U.S. Pat. No. 5,922,253, entitled xe2x80x9cProduction Scale Method of Forming Microparticlesxe2x80x9d and U.S. Pat. No. 5,019,400, entitled xe2x80x9cVery Low Temperature Casting of Controlled Release Microspheres,xe2x80x9d the technology described therein also known as Prolease(copyright). All of the above-identified patent applications are assigned to Alkermes Controlled Therapeutics, Inc. of Cambridge, Mass., and are incorporated herein by reference.
Degradable polymers have also been used in other biomedical applications, including use as polymer scaffolds for tissue engineering. In this biomedical application, porous polymer scaffolds are shaped into articles for tissue engineering and tissue guided regeneration and repair applications, including reconstructive surgery. Scaffold applications include the regeneration of tissues such as nervous, musculoskeletal, cartilaginous, tendenous, hepatic, pancreatic, ocular, integumentary, arteriovenous, urinary or any other tissue forming solid or hollow organs. Scaffolds have been used as materials for vascular grafts, ligament reconstruction, adhesion prevention and organ regeneration. In one embodiment, the polymer scaffold provides physical support and an adhesive substrate for isolated cells during in vitro culturing and subsequent in vivo implantation in the human body. An alternate use of degradable polymer scaffolds is to implant the scaffold directly into the body without prior culturing of cells onto the scaffold in vivo. Once implanted, cells from the surrounding living tissue attach to the scaffold and migrate into it, forming functional tissue within the interior of the scaffold. Regardless of whether the scaffold is populated with cells before or after implantation, the scaffold is designed so that as the need for physical support of the cells and tissue diminishes over time, the scaffold will degrade. Degradable polymer scaffolds are described, for example, in U.S. Pat. No. 6,103,255, entitled xe2x80x9cPorous polymer scaffolds for tissue engineering,xe2x80x9d and is incorporated herein by reference.
Additional biomedical applications for synthetic biodegradable polymers include use with fracture fixation, for example, as absorbable orthopedic fixation devices. In particular, such biodegradable polymers permit treatment of bone fractures through fixation, providing good tissue/material compatibility, and facile molding (into potentially complex shapes) for easy placement. Controlled degradation of the polymers permits optimum bone function upon healing. The materials can reestablish the mechanical integrity of the bone and subsequently degrade to allow new bone formation to bear load and remodel. These biodegradable polymers maintain mechanical integrity while undergoing a gradual degradation and loss in size permitting bone ingrowth. In contrast to the traditional use of steel fixation devices, the degradable polymer-based device is advantageous in those situations where the device is not needed permanently or would require removal at a later point in time. Also, metallic orthopedic devices shield stress during healing and can lead to bone atrophy. Polymers for use in such orthopedic applications are described in U.S. Pat. No. 5,902,599, entitled xe2x80x9cBiodegradable Polymer Networks for Use in Orthopedic and Dental Applications,xe2x80x9d and U.S. Pat. No. 5,837,752, entitled xe2x80x9cSemi-Interpenetrating Polymer Networks,xe2x80x9d both of which are incorporated herein by reference. U.S. Pat. No. 5,902,599 also describes synthetic biodegradable polymers for use in dental applications.
The wide variety of commercial and biomedical applications just described for synthetic degradable polymers demonstrates the need for the development of multiple types of polymers with varying degradability profiles.
Synthetic polymers for use in commercial applications are legion. For example, polyethylene, polypropylene, and polystyrene are commercially produced polymers wherein monomer units of ethylene, propylene, and styrene, respectively, are sequentially added to a growing polymer chain by a process known as addition polymerization. The incorporation of monomer units into the polymer continues until the polymerization process is terminated by the addition of a compound that reacts with the end of the polymer chain and which itself is incapable of polymerization, thus quenching the polymerization.
Dacron is a commercial polyester synthesized by the condensation polymerization reaction of dimethyl terephthalate and ethylene glycol. With condensation polymerization, monomers are heated together in order to combine or condense them, forming a polymer. In addition to the formation of the polymer, a small organic by-product is also formed and is known as an elimination by-product. To form Dacron, the dimethyl terephthalate condenses with the ethylene glycol to form the polyester polymer and methanol as the elimination by-product.
A drawback to these mechanisms of generating commercial polymers is the reaction conditions under which polymerization occurs. Typically, high temperatures and pressures are required in order to induce polymerization. Because such severe conditions are required, only monomers that are able to withstand those temperatures and pressures can be used. Such monomers generally possess limited functionality, for under the severe reaction conditions, any functionality present on the monomer in the form of substituents would most likely be eliminated or cleaved from the monomer and/or the polymer. These restrictions on incorporating functionality into polymer systems have limited the ability to synthesize polymers with certain desirable properties, such as degradability generally, and biodegradability specifically. The latter is important if the polymer is to have medical applications as discussed above.
Of course catalysts are known to be used in polymerization reactions in order to avoid the high polymerization temperatures and pressures described above. A catalyst is used to facilitate polymerization by lowering the energy barrier that reacting monomers must overcome in order to initiate polymerization. The catalyst is often a metal or organometallic compound, which reacts with the monomers, but is not itself incorporated into the final polymer structure. But while catalysts can improve polymerization reaction conditions, catalysts cannot by themselves solve the problem of increasing functionality in the resulting polymer, particularly if the monomers themselves are incapable of supporting functionality themselves. Thus, a need remains for an acceptable method of synthesizing functionalized polymers under mild conditions with desirable characteristics such as enhanced degradability.
Synthetic degradable absorbable polymers already developed to date for use in biomedical applications include, for example, poly(p-dioxanone), which is an alternating ether-ester polymer, and its copolymers; polycaprolactone; polyhydroxyalkanoates; poly(propylene fumarate); poly(ortho esters); other polyesters including poly(block-ether esters), poly(ester amides), poly(ester urethanes), polyphosphonate esters, and polyphosphoesters; polyanhydrides; polyphosphazenes; poly(alkylcyanoacrylates); and polyacrylic acids, polyacrylamides, and their hydrogels. These synthetic absorbable polymers are discussed in detail in Handbook of Biodegradable Polymers, edited by Domb, Kost, and Wiseman (Harwood Academic Pub. 1997), incorporated herein by reference. Specifically, chapter 6 discusses poly(ortho esters) and chapter 7 discusses other functionalized polyesters. However, the ability to incorporate functionality into the polyester is limited by the low reactivity of the functionalized monomers. Using as an example monomeric precursors for poly(ester amides), it is known that functionalized morpholine-2,5-diones, known as depsipeptides, can be synthesized by the condensation of xcex1-hydroxy acid with an xcex1-amino acid. These derivatized depsipeptides can be copolymerized with lactones; however, less than 1% of the functionalized depsipeptide monomers are incorporated into the resulting copolymer. Thus, there is a need for new synthetic routes to functionalized polyester polymers.
In addition, synthetic polymers based on the polymerization of caprolactone, lactic acid, and glycolic acid have become mainstays in the field of degradable polymers, in particular the field of degradable polyesters, and are available commercially. Caprolactone is the cyclic ester derivative of caproic acid, CH3(CH2)4CO2H, and can be ring-opened to form the polyester poly(caprolactone), xe2x80x94[(CH2)5CO2]xe2x80x94. It should be noted that caprolactone has two structural isomers, designated xcex5 and xcex4 caprolactone. Any discussion of caprolactone generally applies to both forms, unless specifically noted. Lactic acid- and glycolic acid-based polymers with high molecular weights are not obtained through direct condensation of the corresponding carboxylic acid due to reversibility of the condensation reaction, backbiting reactions, and the high degree of conversion required. Rather, lactic acid- and glycolic acid-based polymers are typically obtained by ring-opening polymerization of the corresponding diester dimers, lactide and glycolide, respectively, themselves. Alternatively, the reaction can be carried out as a condensation of lactic and glycolic acid. The resulting polymers of these polymerization reactions are poly(lactic acid), also referred to as poly(lactide), abbreviated PLA and poly(glycolic acid), also referred to as poly(glycolide), abbreviated PGA. Copolymers incorporating both monomers are also available and are termed poly(lactide-co-glycolides) abbreviated PLGA and poly(glycolide-co-lactides) abbreviated PGLA, or collectively PLGs. U.S. Pat. No. 5,650,173, incorporated herein by reference, describes examples of these commercially available polymers and copolymers based on lactic acid and glycolic acid. It should be noted that lactide has two structural isomers, denoted D and L. Any discussion of lactide generally is referring to a racemic mixture of both isomers, i.e., d,1-lactide, unless specifically noted.
In addition to the polymers based solely on caprolactone, lactic acid and glycolic acid, degradable polymers can be synthesized in which additional monomer units are incorporated into the backbone of poly(caprolactone), PLA, PGA, or PLGs. In particular, copolymerization with preformed polymers having a hydrophilic segment can be used. Such hydrophilic segments include any number of segments based on diol- or glycol-containing linkages, for example, polyethylene glycol (PEG), also known as polyethylene oxide (PEO), polypropylene oxide (PPO), and pluronics. The resulting copolymers, thus include lactide and/or glycolide monomer units along with the polyether hydrophilic core initiating segment as a single block in the backbone of the polymer. For example, a PEG with molecular weight of 600 would consist of a block of at least 13 monomer units. Other polymers have multiple large segments or blocks of PEG alternating with blocks of a polyester. For example, Polyactive(copyright), is a copolymer that has large blocks of PEG alternating with blocks of poly(butylene terephthalate).
All of these polymers and copolymers derived from caprolactone, lactic and glycolic acid, with or without additional hydrophilic segments, contain ester linkages in the backbone of the polymer chain. The presence of this ester linkage provides the necessary functionality to permit degradability, particularly biodegradability. As opposed to other linkages, such as amides, which require severe conditions in order to decompose, the ester linkage undergoes hydrolysis under even mildly basic conditions such as those found in vivo. In contrast, the amide linkage requires more stringent conditions and is not easily hydrolyzed even under strongly acidic or basic conditions. In vivo, the only available route for cleavage of an amide bond is enzymatic, and that cleavage is often specific to the amino acid sequence. The highly crystalline nature of polyamides, e.g., nylon, further slows degradation by preventing or blocking access to the amide bond by water molecules and enzymes.
However, all of these polyester polymer formulations just described for biomedical applications suffer from a number of disadvantages. It is true that polymerizations involving ring-opening polymerization of caprolactone, lactide, and glycolide occur under milder conditions compared to the industrial, commercial polymerizations of ethylene, propylene, styrene, and dimethyl terephthalate. Nevertheless, like those commercially generated polymers, polymers generated by ring-opening polymerization of caprolactone, lactide, and glycolide lack the ability to support a wide variety of structural functionality, which in turn restricts their functional versatility. This is because the cyclic ester caprolactone and the dimeric cyclic esters, lactide and glycolide, themselves are incapable of supporting a wide variety of functionality, thus precluding incorporation of such functionality into the polyester polymer, even though the polymerization occurs under relatively mild conditions.
The synthesis of functionalized polymers is the key to the development of a new generation of degradable polymers for commercial and biomedical applications. The ability to incorporate more varied structural features into the polymer permits increased functionality and uses for the polymer in a wider variety of applications. As the above discussion demonstrated in the context of biomedical applications, degradable polymers are presently used for matrices for delivery of bioactive substances, for use as scaffolding in tissue engineering, for use as sutures, for fracture fixation, in dental applications, as sealants, as well as in other applications. However, the full potential of this family of polymers based on cyclic ester monomers cannot be realized given the restrictions on incorporation of structural functionality into the polymer.
Control over functionality will also permit greater control over polymer degradation. Biodegradability, as well as biocompatibility, of polymers are important characteristics if the polymer is to be used for biomedical applications as discussed above. The creation of polymers in today""s society and the exponential use in all areas of society has also created environmental concerns over whether such polymers will degrade or will end up in landfills forever. Biodegradability of polyester polymers depends on the ability of the ester linkage in the polymer backbone to hydrolyze, that is, to decompose in the presence of water. The ability of that linkage to hydrolyze, and the time frame over which such decomposition occurs, is influenced by the surrounding substituents. Thus, control over the functionality introduced into the polymer through selection of appropriate substituted monomers will greatly affect the ability to control the degradation of the polymer.
Incorporation of functionality also allows greater processing options for use in various applications. Being able to control what types of substituted monomers can be incorporated into the polymer allows control over the physical characteristics of the resulting polymer. Those physical characteristics are important in determining the consistency of the polymer and what types of processing steps the polymer can withstand. This in turn will determine to what applications particular polymers will be most suited.
For example, including functionality attached to the polymer backbone that can be crosslinked, such as through photocuring, radiation, or by chemical means, will produce polymers with the desirable physical characteristics of having high mechanical strength while having a low molecular weight. Examples of such cross-linkable polymeric systems are the following: U.S. Pat. No. 5,626,863, issued to Hubbell et al., entitled xe2x80x9cPhotopolymerizable Biodegradable Hydrogels as Tissue Contacting materials and Controlled-Release Carriersxe2x80x9d; U.S. Pat. No. 5,844,016, issued to Sawhney et al., entitled xe2x80x9cRedox and Photoinitiator Priming for Improved Adherence of Gels to Substratesxe2x80x9d; U.S. Pat. No. 6,051,248, issued to Sawhney et al., entitled xe2x80x9cCompliant xe2x80x9cTissue Sealantsxe2x80x9d; U.S. Pat. No. 6,153, 211, issued to Hubbell et al., entitled xe2x80x9cBiodegradable Macromers for the Controlled Release of Biologically Active Substancesxe2x80x9d; U.S. Pat. No. 6,201,065, issued to Pathak et al., entitled xe2x80x9cMultiblock Biodegradable Hydrogels for Drug Delivery and Tissue Treatment.xe2x80x9d All of the aforementioned patents are incorporated herein by reference.
As another example, control over the functionality also permits design of polymers capable of undergoing phase transitions when in contact with physiological conditions. One type of such polymers is a liquid at room temperature but gel at body temperatures, i.e., so-called thermoresponsive polymers, which enhances ease of injection of the polymer into a human or animal body. Such polymer systems are discussed, for example, in U.S. Pat. No. 5,702,717, issued to Cha, et al., entitled xe2x80x9cThermosensitive Biodegradable Polymers Based on Poly(Ether-Ester) Block Copolymers,xe2x80x9d and U.S. Pat. No. 6,004,573, issued to Rathi et al., entitled xe2x80x9cBiodegradable Low Molecular Weight Triblock Poly(Lactide-Co-Glycolide) Polyethylene Glycol Copolymers Having Reverse Thermal Gelation Properties,xe2x80x9d both of which are incorporated herein by reference. A second type of polymer capable of undergoing such phase transitions involves injection of polymer dissolved in a solvent, which after introduction into the body, the solvent is replaced by water, resulting in solidification of the polymer. Such polymer systems are exemplified by U.S. Pat. No. 5,968,542, issued to Tipton, entitled xe2x80x9cHigh Viscosity Liquid Controlled Delivery System as a Devicexe2x80x9d; U.S. Pat. No. 6,143,314, issued to Chandrashekar et al., entitled xe2x80x9cControlled Release Liquid Delivery Compositions with Low Initial Drug Burstxe2x80x9d; and U.S. Pat. No. 5,340,849, issued to Dunn et al., entitled xe2x80x9cBiodegradable In-Situ Forming Implants and Methods for Producing the Same,xe2x80x9d all three patents incorporated herein by reference. An additional example of the benefits of control over the functionality and hence the physical properties of the polymer is the ability to have greater control over the diffusion or penetration of water into the polymer. This permits control over the degree of bulk versus surface erosion of the polymer, which is controlled in part by the hydrophilic-lipophilic balance (HLB) in a system.
Attempts have been made to incorporate epoxides into various polymer systems. Epoxides are known to undergo ring-opening polymerization, a process which takes advantage of the fact that cyclic monomers inherently have associated ring strain, which is inversely proportional to the size of the ring. The greater the ring strain, the less energy required to open the ring, and the milder the reaction conditions necessary to achieve polymerization. However, even though the ring-strain associated with epoxides facilitates ring-opening, epoxides require basic conditions in the presence of a solvent in order to effect polymerization. Any functionality on the epoxide will be removed as a result of exposure to the basic solvent system. Also, polymerization under these conditions does not permit control over the polymerization itself due to random hydrolysis of chemical bonds. Thus, even though epoxides may be functionalized with various substituents, polymerization under mild conditions to maintain that functionality in the resulting polymer remains elusive.
One example of using epoxides to produce copolymers is described in U.S. Pat. No. 4,195,167, issued to Knopf et al., entitled xe2x80x9cGradient Polymers of Two or More Cyclic, Organic, Ring-Opening, Addition Polymerizable Monomers and Methods for Making Same.xe2x80x9d This patent describes the formation of copolymers of ethylene oxide and propylene oxide using a basic catalyst, e.g., potassium hydroxide, at temperatures above 100xc2x0 C.
Another example of using epoxides to produce copolymers is described in U.S. Pat. No. 6,221,977, issued to Park et al., entitled xe2x80x9cBiodegradable Aliphatic Polyester Grafted with Polyether and a Process for Preparing the Same.xe2x80x9d This patent describes the formation of grafted polymers wherein an epoxide, i.e., epichlorohydrin, is reacted with polyethyleneglycolmethylether (PEGME), to form an epoxide substituted with a polyether linkage. That substituted epoxide is then reacted with an ester to form a polyester polymer grafted to a side chain composed of PEGME through an ether linkage.
Another example involving epoxides to produce copolymers is described in an article by Jeong et al., entitled xe2x80x9cThermogelling Biodegradable Polymers with Hydrophilic Backbones: PEG-g-PLGA,xe2x80x9d in Macromolecules, 2000, 33, 8317-22. That article describes the sequential synthesis of a copolymer using preformed PEG in the backbone grafted to side chains derived from lactide and glycolide.
Another example where epoxides have been used to form copolymers is described in U.S. Pat. No. 5,359,026, issued to Gruber, entitled xe2x80x9cPoly(Lactide) Copolymer and Process for Manufacture Thereof.xe2x80x9d That patent describes copolymerization of lactide with an epoxidized fat or oil, e.g., linseed oil, for the purpose of forming copolymers with improved processing properties. However, the epoxides disclosed in that patent are not functionalized. Moreover, those epoxides are actually multiple epoxides (polyepoxides), rather than monomeric epoxides, when reacted with lactide, requiring temperatures in excess of 180xc2x0 C.
Because at present synthesis of polymers with particular functionality is limited as a result of the conditions under which polymerization occurs and/or as a result of the limited structural functionalization possible of the reactant monomers themselves, there is a need in the art to develop synthetic methods to create polymers with a wider variety of structural functionalization. There is a further need in the art to synthesize such polymers so as to enhance the ability to control the degradation of the polymers in commercial and biomedical applications.
The present invention, the description of which is fully set forth below, solves the need in the art for development of such functionalized, degradable polymers.
The present invention provides for the synthesis of various functionalized polymers. The functionalized polymers are synthesized through the process of ring-opening polymerization. Polymerization occurs under mild conditions. The functionalization of the polymers permits control over certain properties of the polymers, in particular, the degradation of the polymers.
In one embodiment of the invention, functionalized epoxides are synthesized for use as monomers in polymerization reactions. These functionalized epoxide monomers can be viewed as having the structure Exe2x80x94CHRxe2x80x94G. In this structural representation, E represents the epoxide moiety itself, i.e., 
the three-membered cyclic ether structure typical of epoxides. R represents hydrogen or any alkyl group. G represents a derivatizable group. The derivatizable group can contain any functional group capable of bonding to the (Exe2x80x94CHR)xe2x80x94 moiety and can contain a wide variety of functionality. Such derivatizable groups can include a degradable moiety, i.e., one that is susceptible to decomposition under appropriate conditions, such as neutral, acid, or base hydrolysis.
In a further embodiment of the invention, the above-described functionalized epoxides are polymerized by ring-opening polymerization. The ring-opening polymerization occurs under mild conditions using an initiating system. The initiating system of the present invention includes any system capable of ring-opening polymerization.
The homopolymer resulting from the ring-opening polymerization of the functionalized epoxides is comprised of repeating ethoxy ether units, i.e., the ring-opened 
epoxide moiety, with the functionalized side chain of the original functionalized epoxide, i.e., the derivatizable group G, appended to one of the carbon atoms of each of the repeating ethoxy ether units. Because use of the initiating systems of the present invention permits polymerization under mild conditions, the side chain can support a wide variety of structural functionalization, as noted above in the discussion of the synthesis of the functionalized monomer units. The present invention contemplates such homopolymers containing side chains linked to the backbone of the polymer through a degradable linkage.
In addition to the above-described synthesis of functionalized epoxides before subsequent polymerization to form a homopolymer, the present invention contemplates functionalizing the side chain of the epoxide after the epoxide has been ring-opened and the polymer formed. In this sense, the epoxide is functionalizable or derivatizable, rather than already functionalized or derivatized.
In still another embodiment of the invention, ring-opening polymerization is used to copolymerize the above-described functionalized epoxides with cyclic esters. The ring-opening polymerization occurs under mild conditions, using an initiating system. The initiating systems that can be used for these copolymerization reactions are the same as those described above for the homopolymerization reactions. Preferably, the initiating system comprises an organotin catalyst and an alcohol-containing species. The resulting copolymer is comprised of both the ring-opened functionalized epoxide, in the form of ethoxy ether units, and the ring-opened cyclic ester, in the form of ester units. The functionality of the epoxide monomer can be as described above. The present invention contemplates copolymers containing side chains linked to the backbone of the copolymer through a degradable linkage. The ethoxy ether units are randomly distributed throughout the polyester polymer backbone. A random distribution of ethoxy ether units in the backbone means that there are no large regions of exclusively either polyester units or polyethoxy ether units that would otherwise impart dominant physical characteristics, e.g., hydrophilicity or hydrophobicity, on a microscopic level. Rather, the ethoxy ether units are incorporated proportionally into the polymer backbone based on the amount of functionalized epoxide in the feed initially. Stated another way, no regions containing exclusively sequential ethoxy ether units are present in the backbones of the polymers of the present invention, such that an ethoxy ether unit is repeated no more than 10 times, preferably no more than 7 times, more preferably no more than 6 times, and most preferably no more than 5 times The cyclic ester monomer can be any cyclic ester susceptible to ring-opening polymerization. Preferably, the cyclic ester is either lactide, glycolide, caprolactone, 1,4-dioxan-2-one, or a cyclic carbonate.
In addition to the above-described synthesis of functionalized epoxides before subsequent polymerization to form a copolymer with cyclic esters, the present invention contemplates functionalizing the side chain of the epoxide monomer after the epoxide has been ring-opened and the copolymer with the ring-opened cyclic ester formed.
Viewed from a further aspect, the present invention provides for functionalizing the epoxide to provide for greater control over the degradation of the resultant homopolymer. Similarly, the present invention provides for functionalizing the epoxide to provide for greater control over the degradation of the resultant copolymer when the functionalized epoxide is polymerized with cyclic esters.
Viewed from yet a further aspect, the present invention relates to improved methods of preparing a pharmaceutical composition in particulate or capsule form. In one aspect of the invention, the pharmaceutical composition is designed for the controlled release of an effective amount of an active agent over an extended period of time. The methods of the present invention may be carried out using preformed particulates, or may additionally comprise the production of the particulates.
Viewed from still another aspect, the present invention relates to methods of using the functionalized homopolymers and copolymers in various applications. In one aspect of the invention, the functionalized polymers as described herein can be used for biomedical applications such as orthopedic and dental applications, prosthetic devices, tissue sealant and wound healing, tissue engineering, and bone replacement/healing. In another aspect of the invention, the functionalized polymers described herein can be used as environmentally friendly polymers.
Features and Advantages
The present invention advantageously can be used for the synthesis of functionalized degradable polymers heretofore unavailable through standard synthetic methods. The synthetic methods of the present invention are easily adaptable to existing polymer synthesis protocols. The present invention offers the ability for extensive and diverse functionalization of the parent polymer system due to the ease of synthesis of a wide variety of functionalized epoxide monomers, allowing for easy derivatization either before or after polymerization.
Another advantage of the present invention is that the functionalized epoxide monomers described herein, can aid in the solubilization of other monomers in copolymerization reactions due to the fact that the functionalized epoxides are typically liquids, thus, allowing for the use of milder polymerization conditions. Those other monomers include molecules such as lactide, glycolide, and any other monomer that requires either high temperatures to induce melting or the use of secondary solvents. The solubilization properties of the functionalized epoxides allow for mild copolymerization reaction conditions, i.e., lower reaction temperatures and pressures, and milder catalyst systems. Not requiring a separate solvent phase in which to carry out the polymerizations greatly enhances the ability to retain functionality in the resulting polymer by avoiding any possible detrimental side reactions between the solvent and the monomers as well. The solubilization by the functionalized epoxide also permits formation of copolymers in a single step, rather than sequentially involving numerous steps.
Additionally, because the result of the copolymerization of the functionalized epoxide and the cyclic ester is a polymer backbone that is a derivative of both polyethylene oxide and cyclic esters (i.e., the standard synthesis of degradable polyesters), toxicity issues should be minimal, if not nonexistent. Although polymers consisting of both polyether and polyester are known, the polyether exists as only a few higher molecular weight segments which are nondegradable, whereas the copolymers of the present invention result in ether functionality distributed throughout the polyester. This allows the copolymer to be degraded into smaller molecules, e.g., having a molecular weight less than 600, which are more easily metabolized or eliminated by the body.
Another advantage of the present invention is that the incorporation of functionalization into the polymer provides for the enhanced control over the physical characteristics of the polymer, in particular, polymer degradation. The ability to control these physical characteristics offers enhanced control over the hydrophilicxe2x80x94lipophilic balance (HLB) in a given polymer system, which can affect the rate of water uptake, which is one of the parameters that plays a role in the trade off between bulk degradation and surface degradation of a polymer.
Also, control over functionalization provides for improved polymer processing and use in a greater diversity of potential applications. The functionalized polymers of the present invention can be processed to form particulates for delivery of active agents in pharmaceutical applications. Certain functionalized polymers with unsaturated substituents can be crosslinked, even in vivo, to form polymer networks for high strength applications. Other functionalized polymers can be synthesized to form thermoresponsive polymer gels, so that a liquid polymer at room temperature becomes a gel or a solid once it is injected into a human or animal body, facilitating the ease of injection.